REVIEW
Ultraviolet Radiation and the Anterior Eye
Minas Coroneo,
Abstract: The eye is on the one hand dependent on visible light energy and
on the other hand can be damaged by these and the contiguous ultraviolet
(UV) and infrared wavelengths. Diseases of the eye in which sunlight has been
implicated have been termed the ophthalmohelioses, and these conditions pose
a significant problem to the eye health of many communities. The ophthalmohelioses have a tremendous impact on patients’ quality of life and have
significant implications on the cost of health care. Although cataract is not
entirely caused by insolation, it now seems certain that sunlight plays
a contributory role—cataract extraction is one of the, if not the most, commonly performed surgical procedures in many societies. Pterygium, typically
afflicting a younger population, adds a tremendous burden, both human and
financial, in many countries. We review evidence that peripheral light focusing
by the anterior eye to the sites of usual locations of pterygium and cataract
plays a role in the pathogenesis of these conditions. Recognition of the light
pathways involved with foci at stem cell niches has directed our investigations
into inflammatory and matrix metalloproteinase-related pathophysiologic
mechanisms. An understanding of the intracellular mechanisms involved has
provided some insight into how medical treatments have been developed for
the effective management of ocular surface squamous neoplasia. The concept
of peripheral light focusing has also provided direction in the prevention of
these diseases. This has resulted in improved sunglass design and the further
development of UV-blocking contact lenses. With the development of ocular
UV fluorescence photographic techniques, we have been able to demonstrate
preclinical ocular surface evidence of solar damage. Evidence that diet may
play a role in the development of certain conditions is reviewed. The conundrum of the public health message about solar exposure is also reviewed,
and in this context, the potential role of vitamin D deficiency is summarized.
The eye may play a role in the development of individualized assessment
techniques of solar damage, perhaps allowing us to provide better advice to
both individuals and populations.
Key Words: Ultraviolet—eye—Pterygium—Cataract—Ocular surface
squamous neoplasia—Dysphotopsia—Sunglasses—Contact lens—Sun
protection.
(Eye & Contact Lens 2011;0: 000–000)
From the Department of Ophthalmology, University of New South
Wales, Sydney, Australia.
Disclosure: The author discloses that he is the inventor of US Patent
7,217,289: Treatment of photic disturbances in the eye, US Patent
7,846,467: Ocular scaffold for stem cell cultivation and methods of use,
US Patent application 20060204474: Treatment of epithelial layer lesions,
US Patent application 20050287115: Treatment of ocular lesions; is
a consultant to Allergan, Inc in the area of medical treatment of pterygium
and dry eye and has received research funds and travel support; receives
royalties from Eagle Vision Inc in relation to a dry eye product; and has been
a consultant to Johnson and Johnson Vision Care Inc and has received
research funds and travel support..
Address correspondence and reprint requests to Minas Coroneo, M.Sc.,
M.S., M.D., Department of Ophthalmology, Prince of Wales Hospital, High St.
Randwick, NSW 2031, Sydney, Australia; e-mail: M.Coroneo@unsw.edu.au
Accepted May 6, 2011.
DOI: 10.1097/ICL.0b013e318223394e
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M.Sc., M.S., M.D.
A
s the terrestrial invasion by amphibians commenced,
an essential adaptation was the development of filters
to screen out more energetic wavelengths that were absorbed by
the surface layers of the marine environment. Although perhaps
relatively effective, at least in creatures with relatively short life
spans, the vast array of conditions, particularly those that afflict the
human eye suggests that only a partial solution to this problem was
engineered. In one sense, these conditions, particularly of the
anterior eye, can be seen as evidence of suboptimal adaptation
to terrestrial life. The conditions in which sunlight has been
implicated (with varying degrees of certainty) in the pathogenesis
have been termed the ‘‘ophthalmohelioses’’1,2 (Table 1) as the
ophthalmic correlate of the dermatohelioses.
This group of conditions has been of great interest to Australian
ophthalmologists for reasons of history and climate. In Australia’s
first medical publication of 1840,3 it is stated, ‘‘In this climate the
eye is more liable to be affected than in England. There is a Sun that
for many months in the year shines with a power and a brilliancy,
that ‘‘at home’’ we are not cognizant of.’’ Ida Mann, first
Professor of Ophthalmology at Oxford, during her years
in Australia recounts that it ‘‘is the land of sin, sand, sorrow and
sore eyes . it’s the climate.’’4 Kerkenezov5 in 1956 was the first
to observe that white people with pterygia suffered from
hyperkeratoses and rodent ulcers—an early clinical indication
of the role of ultraviolet (UV) radiation. Further, pterygia developed
about a decade before the dermatohelioses. Thus, an early link was
made between UV insolation and both pterygium and skin
malignancy—at that time the link with cutaneous melanoma was
being proposed.6 Cameron7 author of one of the few monographs
on the subject, recognized that pterygium was most common
between latitudes 40!N and 40!S and for island populations. Thus,
a relative !pterygium belt" straddles the equator, paralleling local
atmospheric UV energy intensity. Yet, much of the UV light that
strikes the eye is reflected, indirect light (albedo) and the elegant
studies of Urbach,8 demonstrated that reflected light struck the eyes.
It was therefore not surprising that the ophthalmohelioses were
prevalent in places of high ground reflectance or in individuals
exposed under these conditions. This may explain why there is
a pterygium prevalence of 8.6% in Greenland9,10 at 61!N of the
equator (compare 7.3% in the Australian Blue Mountains11) where
there is less than a third of direct UVB found in the equatorial
regions. Ultraviolet exposure may thus be similar if terrain
reflectivity is taken into account.12 Also, because of the indirect
and geometric nature of this exposure (vide infra), individual
exposure is likely to have been inaccurately estimated from the
standard questionnaires used in epidemiologic studies13—individual exposures and factors peculiar to individuals could result in
underestimation of exposure.
1
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M. Coroneo
The prevalence of pterygium has been relatively high as Australia’s
first full-time ophthalmologist, Evans14 reported on a new operation in
1893—a tradition continued by D’Ombrain15 in 1948. He noted ‘‘I
have pinguecula in both eyes; they formed in my twenty-second year
when I possessed my first motor bicycle and before I learnt the wisdom
of wearing goggles; my late father, an ophthalmic surgeon, noticed the
pinguecula and made me wear goggles.’’ This was perhaps early
recognition of the importance of side light in ocular UV exposure and
the fact that conventional spectacles offer inadequate protection.
Another early observation that side light rather than direct light is
important in pterygium pathogenesis is that pterygium is found in the
fixing eye of patients with exotropia where it is expected that the
nasal region of the exotropic eye be more exposed.16 In extremely
bright light, the nondominant eye is closed, explaining why
pterygium initially afflicts the dominant eye.17
Work from our unit in the 1980s described high pterygium
prevalence rates in Indigenous Australians, approximately 15% in
older age groups as compared with 6% to 12% in nonaborigines.18
This was believed to be because aborigines ‘‘spend all their waking
hours outdoors caus[ing] them to be more exposed to solar
radiation.’’ Yet, in examining 200 Aborigines in South Australia
in 1888, the author was ‘‘struck with the absence of Pterygium
in individuals so exposed.’’19 Although speculative, it is possible
that this earlier population had not been exposed to trachoma
(unlike their 1980 counterparts20), a disease known to affect the
limbus,21 after which, pterygium has been associated22 and
observed to develop.23 These observations raise the possibility
that a double insult to the limbus (and corneal epithelial stem cells),
infection then UV exposure may increase the risk of developing
pterygium. Another possibility is the Westernization of the diets
of Indigenous Australians, with a resultant reduction in protection
from UV light (vide infra).
Another intriguing aspect of pterygium research is the lack of
an animal model. This may be because the human eye has a unique
morphology whereby the sclera and limbus are exposed,24,25
whereas in most other species, the eyelids cover the limbus
or the limbus is heavily pigmented and therefore protected from
exposure to light. Humans also have large temporal visual field that
not only aids survival but also acts as a large collecting zone for
UV light, incident on the temporal limbus.
In addition to the potentially harmful effects of normal levels of
sunlight on the eye, there have also been concerns about the ozone hole
and the ophthalmic consequences of increased ocular UV insolation.26
PERIPHERAL LIGHT FOCUSING AND
PTERYGIUM PATHOGENESIS
During my first weeks as an ophthalmology trainee in 1982,
I noticed that light incident from the side was focused by the
anterior eye to areas in the nasal aspect of the eye and ocular
adnexa. I was putting on a necktie a day or so after my Departmental
Chair had commented on what he considered to be my overly
formal dress when this observation was made. At the time,
in studying optics, I had learned about the related phenomenon
of sclerotic scatter whereby light was believed to traverse the cornea
by a pathway of internal reflection. I subsequently discovered that
foci at the nasal limbus had been noted earlier; however, foci at the
2
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eyelid margin and on the nasal equator of the crystalline lens had
not been observed. There was a realization that the usual (nasal)
location of pterygium and pinguecula coincided with an intense
focus of peripheral light and that light damage to limbal structures
(including corneal epithelial stem cells27) would be important
in pathogenesis (Fig. 1).
In initial studies,28–30 we determined pathways by which the
anterior eye, acting as a side-on lens, focuses light onto the opposite
side of the eye, most noticeably to the distal (nasal) limbus (type 1
phenomenon). Light proceeds across the anterior eye by traversing
the anterior chamber and not by the so-called sclerotic scatter. The
degree of limbal focusing is determined in part by the corneal shape
and anterior chamber depth, and this may explain, in part, why
particular individuals in a particular environment are afflicted. The
transcameral light pathways were confirmed using computer-assisted
optical ray–tracing techniques.31–33 We calculated that the peak
light intensity at the distal limbus is approximately 20 times that of
the incident light intensity29—this has further been refined in
subsequent studies to take into account corneal shape31,32 and
focusing on the crystalline lens.33 The limbal effect peak intensity
was found at an incident angle of 104!.33 Furthermore, it seems that
the light focus is actually not a spot but a complex arc
shape—explaining why it is difficult to appreciate when viewing
along the path of incident light.
The earliest report of peripheral light focusing (PLF) is from the
work of von Helmholz.34 By asking a subject to accommodate, he was
able to observe a movement of the light focus anteriorly, neatly
demonstrating that the anterior crystalline lens surface (and iris) move
forward during accommodation. Graves35 described a method of
corneal illumination, termed sclerotic scatter, in which light was
presumed to pass horizontally across the cornea by total internal
reflection within the corneal stroma. Although this is considered as
a possible pathway in initial observations,28 initial ray-tracing studies29
determined that this mechanism could not occur. Another early report
from Mackevicius36 linked the observation of a limbal focus to
pterygium pathogenesis. Rizzuti37 used a penlight in keratoconus
patients to illuminate the temporal limbus and noticed distal limbal
focusing. He claimed that this was not seen in normal corneas.
Our calculations predicted that a steeply curved cornea (as is seen
in keratoconus) would be expected to produce an intense distal
limbal focus.31 Furthermore ‘‘normal’’ corneas also produce such
foci. It was noticed in cattle38 that limbal foci occurred and
coincided with the sites of precursor lesions for squamous
carcinoma—ironically we used bovine eyes to work out the optical
pathways involved29 in conjunction with ray-tracing experiments.
Light focusing was again implicated in pterygium pathogenesis,39
but the pathway was believed to be by sclerotic scatter (transcorneal) and the mechanism of pathogenesis to involve damage
to subconjunctival tissue, dellen formation and subsequent
pterygium formation. These previous studies failed to define the
precise optical pathways, the intensity of the limbal focus, the
potential to damage stem cells and the pathophysiologic mechanisms involved (vide infra). They also failed to recognize that
limbal focusing was one of a series of foci induced by the peripheral
optics of the anterior eye.
Although the characteristic location of pterygium is at the nasal
limbus, pterygia can be located temporally. In one series, this was
seen in only 2% of cases,40 yet in one study of sawmill workers,
15% demonstrated temporal pterygium alone, and 11%
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UV Radiation and the Anterior Eye
FIG. 1. Coincidence of the usual location of
ptergium (upper left panel) with an intense nasal
light focus (right and lower panels), after peripheral
light focusing at the nasal limbus.
demonstrated both temporal and nasal pterygia together.41 We have
demonstrated light focusing at the temporal limbus,28 and this
is most easily demonstrated in patients with a low nasal bridge,
possibly explaining why temporal pterygium may be more
prevalent in certain racial groups. In an Arabic population, temporal
pterygium was reported in 2.4% of cases,42 whereas in a Chinese
TABLE 1.
Ophthalmic Conditions in Which Sunlight Has been
Implicated in Pathogenesis
Eyelid
Ocular surface
Crystalline lens
Uvea
Vitreous
Retina
Glaucoma
Ocular posture
Systemic
(conditions with
potential for
ophthalmic
involvement)
Wrinkles; sunburn, photosensitivity reactions,
cicatricial ectropion, dermatochalasis,
premalignant changes, malignancy—BCC,
squamous cell carcinoma, primary acquired
melanosis, melanoma
Pinguecula, pterygium, climatic keratopathy
(Labrador keratopathy), actinic granuloma,
keratitis (flash, snow blindness), arcus, band
keratopathy, corneal endothelial
polymorphism, reactivation of herpetic
keratitis, scleritis in porphyria, senile scleral
plaques, postphotorefractive keratectomy haze,
dysplasia and malignancy of the cornea or
conjunctiva, vernal catarrh
Cataract, anterior capsular herniation, early
presbyopia, capsular pseudoexfoliation,
subluxation in Marfan syndrome, intraocular
lens dysphotopsia
Melanoma, miosis, pigment dispersion, uveitis,
blood–ocular barrier incompetence
Liquification
Photic maculopathy, erythropsia, macular
degeneration, choroidal melanoma, visual loss
with photostress in carotid stenosis, circadian
rhythm disturbances
Experimental
Intermittent exotropia
Xeroderma pigmentosum, BCC, basal cell
nevus syndrome, porphyria cutanea tarda,
polymorphous light eruption, photosensitivity
(drugs, uremia) immunosuppression, myopia,
cranial arteritis, herpes zoster ophthalmicus,
vitamin D deficiency
BCC, basal cell carcinoma.
q 2011 Lippincott Williams & Wilkins
population, this was reported in 6.7% of the cases.43 There was
an early suggestion that a large nose would protect the eye from
sunlight,44 and this seems to be true for peripheral light crossing the
midline in the direction of the temporal limbus.
Apart from renewal of corneal epithelium, the limbus maintains
a barrier so that normally conjunctival and corneal epithelium
remains separated. Although little direct UV light strikes the ocular
surface, with PLF, an intense beam crosses the anterior chamber,
little altered by aqueous humor45 and strikes the basal and relatively
unprotected stem cells. Thus, PLF circumvents the normal
protection of this corneal stem cell niche by the more superficial
limbal cells that normally absorb directly incident light.46 Because
stem cells are pluripotent and capable of division, we postulated that
alteration by UV light could result in a tissue mass of several cell
types that traverse the limbal barrier and invade the cornea. Our
observations are also consistent with the finding that the presence
of a pterygium can be associated with deep corneal changes at the
level of the endothelium and Descemet membrane and that
endothelial cell density may be lower in these eyes.47 Furthermore,
limbal focusing may also affect corneal nerves as they cross the
limbus, allowing the possibility of neuropeptide involvement
in pterygium pathogenesis and explaining corneal sensory alterations in pterygium patients.48 If corneal nerves are implicated, their
radial distribution may also help to explain pterygium shape.
Because the eye provides the only substantial lens focusing
system on the body, pterygium (and perhaps cortical cataract)
would be expected to develop earlier than the dermatohelioses,
explaining Kerkenezov’s5 early observations. Thus, if we are
exposed to increasing amounts of UV radiation, increased
pterygium prevalence may be an early consequence of this
exposure, because the pathologic processes would be sped up
as a result of an exposure of light focused by at least an order
of magnitude by the anterior eye. Pterygium prevalence may turn
out to be a marker for increased human UV insolation.
A second light focusing effect can be observed if the light source
is moved more anteriorly (than the location required to produce
3
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M. Coroneo
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FIG. 2. Coincidence of early onset cortical lens
opacity (lower upper panel) with an intense focus,
evident on the ocular surface (right upper panel) after
transcameral and translenticular passage of focused
peripheral light.
a limbal focus). Light is focused through the pupil (circumventing
the protective effect of the iris) and onto the crystalline lens equator
stem cells (Fig. 2). Light then exits the eye through the vascular
ciliary body and appears as a red spot on the ocular surface.28–30
Ray-tracing studies of these transcameral/translenticular pathways
have confirmed that the peak intensity of visible light varies
between 33.7 and 34.8. Focusing of UVA results in higher peak
intensities of 30.6 to 38.6 with maximum peak intensities
occurring at angles of incidence of 82! to 86!.33,49 The inferonasal
localization of early cortical cataract has been reported as far back
as 1889,50 and this has been confirmed by several subsequent
studies.51,52 Because the germinative zone of the crystalline lens
is located equatorially, this region may be more sensitive to focused
UV radiation than other parts of the crystalline lens.53 This type-2
peripheral focusing effect has also provided an explanation for an
intraocular lens–associated glare phenomenon known as dysphotopsia.54–56 In this phenomenon, the peripheral optics of intraocular
lenses allow a prismatic effect resulting in side light being directed
posterior to the ora serrata so that the far peripheral retina is poorly
illuminated, resulting in a scotoma (or arcs of light, coincident with
retinal foci). This is a relatively common and annoying
phenomenon and these observations may result in improved
intraocular lens design.
This background work has also enabled us to explain the shape
of both pterygium57 and cortical spoke cataract.58 Using computational models, we examined the growth and movement of limbal
epithelial cells and lens cells, respectively. In the case of pterygium,
a focal limbal insult would result in a wing-shaped lesion and for the
crystalline lens, if clusters of germinative cells are caused to opacify,
the resultant cataract is predominantly spoke shaped. A third type of
PLF effect can be demonstrated on the eyelid margin,28 the site of
a stem cell population.59 We postulated that this might account for the
nasal predilection for eyelid skin malignancy.60
Although these focusing phenomena are most easily seen with
visible light, they also occur at 308 nm,28 this is not unexpected
as the cornea transmits significant amounts of these energetic and
biologically active wavelengths (60% of radiation at 320 nm and
80% at 400 nm.45 The association of exposure to broadband UV
radiation and visible light61 with pterygium is therefore not
surprising.
4
In relation to alterations induced in limbal stem cells, we have
demonstrated that Fuchs Flecks, seen ahead of the leading edge
of the pterygium head, contain p63-a-positive epithelial cell
clusters, further evidence that pterygia develop from limbal
epithelial progenitors.62
PATHOPHYSIOLOGY
Although our understanding is incomplete, multiple processes
seem to be involved, and these may be classified as inherited
or individual factors, environmental triggers (UV light, viral
infections) and factors that perpetuate pterygium growth (cytokines,
growth factors and matrix metalloproteinases). These processes are
summarized in Figure 3 and have been extensively reviewed.63–66
In the absence of an animal model for pterygium, we have relied
on cell culture studies and by being the first group to culture
pterygium epithelial cells67 were able to investigate the effects
of UV light at a molecular level. This was a critical step in that we
believed that UV-induced changes in corneal epithelial stem cells
were the driving force behind corneal invasion by the pterygium.
Although other elements, fibroblasts, vascular, neural elements, and
an inflammatory process are involved and mesenchymal–epithelial
interactions,68 we believed it most likely that epithelial cells drive
the process of invasion.
Hallmarks of the pathologic condition of pterygium are the
destruction of Bowman membrane as corneal invasion by the
pterygium proceeds and elastosis, previously interpreted
as evidence of a degenerative process. In attempting to elucidate
how these processes occur, we began by investigating the role
of matrix metalloproteinses (MMPs) in pterygium pathogenesis.69–73
Matrix metalloproteinses are a family of zinc-dependent endopeptidases that are involved in remodeling of the extracellular matrix
and altering cell surface molecules. The actions of MMPs are
counterbalanced by tissue inhibitors of metalloproteinases (TIMPs),
and MMPs are key mediators of photoaging where they regulate
proliferation, cell migration, inflammation, and angiogenesis (see
Chui and Coroneo65). Epithelial cells, fibroblasts, vascular cells and
infiltrating immune cells produce MMPs in pterygia. We have
demonstrated an overexpression of MMPs relative to TIMPs in
the pterygium head and have seen this is a key factor in the invasive
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UV Radiation and the Anterior Eye
FIG. 3. Ultraviolet (UV) light activates multiple
processes that may contribute to the formation of
a pterygium. The UV induces oxidative stress and
epidermal growth factor receptor activation, leading
to production of cytokines, growth factors, and
matrix metalloproteinases. These effector molecules
mediate the influx of inflammatory cells, angiogenesis, proliferation, fibrosis, and extracellular matrix
degradation commonly observed in pterygia (courtesy of Dr. J. Chui).
nature of this condition.67 Several factors, including UV exposure,
cytokines (IL-1 and transforming growth factor-a [TNF-a]) and
growth factors (epidermal growth factor and TNF-a) have been
shown to induce expression of MMPs in pterygium cells.65,66,74,75
The MMP-2 and MMP-9 seem to be associated with disease
progression76 raising the possibility that MMPs could be targeted
in the management of recurrent disease.66 We have also shown that
Gelatinase B (MMP-9) was the most abundant gelatinolytic enzyme
present in tears, elevated approximately twofold in eyes with
pterygia versus the contralateral control eyes.70 This may be
a contributing factor77 to the ocular surface inflammation and dry
eye syndrome seen in pterygium patients78–perhaps presenting
another therapeutic opportunity in treatment with topical
cyclosporine.79 Another potential mode of action of cyclosporine
is by the inhibition of the tachykinin NK1 receptors80 that we have
localized to infiltrating fibroblasts, mononuclear cells and the
epithelia of pterygia.48
In general terms, exposure of cells to UV induces activation
of epidermal growth factor receptors (EGFRs) and subsequent
downstream signaling through the mitogen-activated protein kinase
pathways65,66,81 that are partially responsible for expression
of proinflammatory cytokines, and matrix metalloproteinases
in pterygium cells. Growth factor receptors and associated signaling
pathways are activated as an early response to UV exposure, occurring
independently of ligand binding and believed to involve UVgenerated reactive oxygen species.66 This response is common to the
ocular surface (pterygium) and the skin, where UV induces
phosphorylation and internalization of the EGFR within minutes
of exposure, followed by activation of three mitogen-activated protein
kinase (MAPK) pathways: extracellular signal-regulated kinase
(ERK), c-jun amino-terminal kinase (JNK), and p38. In pterygium,
UV activation of the ERK pathway is shown to induce production of
MMP-1,73,75 whereas activation of the stress-related JNK and p38
pathways contributes to IL-6 and IL-8 induction72 with overexpression of EGFR82 contributing to amplification of these signaling
q 2011 Lippincott Williams & Wilkins
pathways. Transcription factors are induced downstream of EGFR
and MAPK activation, including activator protein-1 (AP-1) and
nuclear factor-kB (NF-kB), which mediate some cellular responses to
UV damage (see 66). The UVB activation of the JNK pathway induces
production of c-Jun and combined with c-Fos forms the AP-1
complex responsible for induction of MMP-1.73 The EGFRinduces
NF-kB activation; however, this is believed to occur through signaling
pathways involving tumor necrosis factor receptor-interacting protein
and NF-kB–inducing kinase. NF-kB mediates UV-induced release
of IL-1, IL-6, and TNF-a from cultured human corneal epithelial cells.
It is therefore possible that UV-induced NF-kB activation may lead to
the induction of these cytokines and growth factors in pterygium.
In extending this work to cataractogenesis, we have demonstrated
specific localization of MMP-1 within lens epithelium and lens
fibers of cortical cataract.83 There was relatively little immunohistochemical staining for MMP-2, MMP-3, and MMP-9 and TIMP-1,
TIMP-2, and TIMP-3 intracellularly within the cortical fibers of
13 cataractous lenses. The inferonasal quadrant contained a proportionally higher number of intracellular lens fibers staining and
intensity of observed staining for MMP-1 The superotemporal
quadrant contained the least number and lowest intensity
of observed MMP and TIMP immunoreactivity. By comparison,
observed immunostaining in control lenses was low for MMP-1,
MMP-2, MMP-3, and MMP-9 and TIMP-1, TIMP-2, and TIMP-3
and was equal in all crystalline lens quadrants. We were also able
to demonstrate that IL-1 and TNF-alpha upregulated the expression
of MMP-2, MMP-3, and MMP-9, and UV-B upregulated the
expression of MMP-1 in a human lens epithelial cell line. These
findings were consistent with the pattern of light focusing onto
a zone of germinative epithelium in which MMP induction can
be demonstrated and which coincides with a known disease pattern.
We also investigated MMP and TIMP activities in the zonular
fibers in normal and Marfan syndrome lenses and demonstrated
positive immunoreactivity for MMP-1, MMP-3, and MMP-9
in Marfan lens zonules, with no evidence of TIMP-1, TIMP-2,
5
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M. Coroneo
or TIMP-3 immunoreactivity.84 In contrast, no MMP-1 or MMP-3
staining was observed in the zonule of normal lenses, but TIMP-1,
TIMP-2, and TIMP-3 were detected. We hypothesized that in the
Marfan syndrome, the product of the defective FBN1 gene
is susceptible to degradation by MMPs as compared with normal
fibrillin (a key component of the zonule) and that the dysregulation
of MMPs and TIMPs results in the progressive damage to the lens
zonules and subsequent lens subluxation. Because in Marfan
syndrome the crystalline lens typically dislocates superotemporally
(as a consequence of weakening of the inferonasal zonule),
we postulated that PLF could result in an increased exposure of the
inferonasal zonule to UV light. This could further reduce fibrillin
expression and perhaps increased MMP expression in this region
resulting in early damage to the zonule, thereby explaining the
pattern of lens dislocation.85
We have also investigated the potential role of MMPs in another
of the ophthalmohelioses, ocular surface squamous neoplasia
(OSSN)86 that often originates at the limbus but can affect the
conjunctiva and cornea. We demonstrated that a higher proportion
of OSSN surgical specimens stained for MMP-1, MMP-3 and
TIMP-2 and TIMP-3 compared with normal conjunctiva.
We established cell lines from tissue explants of both dysplastic
and normal conjunctival epithelial cells and showed that cells
derived from dysplastic tissue are more sensitive to UVB radiation
than normal conjunctival cells. Although in OSSN cells MMP-1
and MMP-3 mRNA expressions were induced by UV in
a mitogen-activated protein kinase–dependent fashion, in normal
conjunctival cells, the same enzymes were upregulated only
at (higher) doses that induced apoptosis.
Ocular surface squamous neoplasia had a tendency to recur after
treatment and traditional surgical procedures such as excision and
cryotherapy are destructive and can have long-term consequences
for the ocular surface.87 Topical treatment with Interferon alfa-2b
which is a well tolerated and generally efficacious has greatly
improved management of OSSN. We have demonstrated a rapid
clinical response to combined treatment with topical interferon alfa2b and all-trans retinoic acid (ATRA), consistent with the
synergistic effects of interferon alfa-2b and ATRA in combination,
both in vitro and in vivo in nonocular neoplasia.87 These
observations stimulated our interest in underlying mechanisms
of action, and using our pterygium model, we have investigated
UV-activated signaling pathways that mediate cytokine and growth
factor production see whether these pathways are sensitive
to blockade by Interferon or ATRA.72 Inhibitors of ERK1/2,
JNK, and p38 MAPKs significantly abolished UVB-mediated
increases in IL-6, IL-8, and vascular endothelial growth factor in
this system. ATRA and Interferon dose dependently abrogated IL-6
and IL-8 but showed no effect on vascular endothelial growth factor
expression after UV exposure, demonstrating a greater antiinflammatory than antiangiogenic response. This area shows some
promise in developing better and less invasive medical treatments
for this group of diseases.66
PREVENTION
The late Professor Fred Hollow, after many years of work
in outback Australia, set out sensible guidelines for preventing these
diseases.88 He addressed issues relating to housing, eye protection and
the likely protective effect of the siesta in certain cultures. Before
6
further considering these factors, two other areas of importance are the
effectiveness of public health campaigns in relation to solar damage
and the identification of individuals at risk of developing these
diseases and a means by which to monitor early sun damage.
Given that Australia has one of the highest skin cancer incidence
and mortality rates in the world,89 the effectiveness of public health
measures is a major concern. A survey of 652 Brisbane students
aged 13–17 years showed only a moderate level of knowledge with
respect to UV, sunlight, and the eyes.90 There was a greater
knowledge about sunlight and body protection than eye protection,
and although 71% of the subjects owned a pair of sunglasses, 81%
of the subjects wore only sunglasses occasionally or not at all. The
reported frequency of wearing sunglasses was significantly related
to personal, family and peer attitudes to such use but not to media
advertising. Australian national surveys during the 1990s of 78,032
students from age 7 to 12 years showed that only 11% of the
students routinely followed all three protective behaviors of
wearing a hat, sunscreen, and clothes that cover the body91 Sun
protection practices among adolescents are suboptimal and have
continued to decline significantly over time. It has been concluded
that future educational programs will require an innovative
approach to modify adolescent behaviors in relation to sun
exposure and sun protection.92 To this end, we have developed
a method that may detect early (preclinical) ocular surface sunlightinduced damage using UV fluorescence photography (UVFP).93,94
We have shown areas of nasal limbal fluorescence in eyes that are
otherwise clinically normal (Fig. 4). These areas of fluorescence are
consistent with focal damage induced by PLF. In a study in schoolaged children, we were able to detect these changes in children from
the age of 9 years. The prevalence of these changes increased with
chronological age, with clinical changes (pinguecula) being noted
from age 13 years. We were surprised to find that in the 12- to
15-year age group, 81% of children showed evidence of damage
(clinical and preclinical). As pointed out, pterygia have been found
to develop about a decade before UV-induced skin conditions and
thus may be an early indicator of increased UV insolation. Changes
detected on UVFP may prove to be the earliest indicator of UV
changes in the body. During the course of these studies, we found
that both the children and their parents were interested in the
changes that we could demonstrate. It may be that this graphic
demonstration of early preclinical and clinical changes of sun
damage will reinforce the important health message to reduce sun
exposure and adopt preventative measures.
By using UVFP, we went on to investigate the patterns of
fluorescence in established pterygia.94 Four patterns were seen—80%
of the patients demonstrated fluorescence at the leading edge of the
pterygium, at the limbus or both. We postulated that the areas of
fluorescence represented areas of cellular activity within the pterygium.
The lack of fluorescence was believed to occur in pterygia that are
‘‘burned out’’ and represent disease that is no longer active.
In relation to housing, on the one hand, it provides shelter from
the elements on the other, modern architecture may allow increased
sunlight indoors and indoor glare can be problematic.88 Some
building materials have a high UV reflectance— in Kenya, hats
were worn indoors in houses with corrugated iron roofs and no
ceilings as ‘‘galvanized sheets did not repel all the sun’s rays’’ or
more likely, result in high levels of scattered UV light indoors.
Corrugated galvanized iron, invented in the 1840s, is a strong, lightweight, corrosion resistant, inexpensive, easily transported material
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Eye & Contact Lens ! Volume 0, Number 0, Month 2011
UV Radiation and the Anterior Eye
FIG. 4. Interpalpebral regions of a 12-year-old girl
who demonstrated an apparently normal ocular
surface (upper panels). The corresponding UV fluorescence photographs (lower panels) demonstrate
areas of fluorescence at the nasal limbus of each eye.
and has been widely used in buildings, but it seems that it highly
reflects UV light. Modern paints resist the elements and may also be
highly reflective of UV light, potentially increasing our exposure
close to, if not in, our shelters.
SUNGLASSES
Sunglasses are usually recommended as a form of protection
against sunlight, yet conventional sunglasses are often a fashion
accessory. However, sunglasses have several added disadvantages:
1. They reduce glare from direct, visible light and may allow
wearers to increase their exposure to UV albedo.30 The eye
is the body’s most efficient light warning system and
represents the only means to caution a person adequately
against the dangers of sunlight, because the skin itself
is not able to announce overexposure rapidly enough
to force its owner to get out of the sun in time. Modern
man has invented remedies for the light sensitivity of the
eye to be able to spend more time in the sun without
feeling uncomfortable.95 In one study, people wearing
sunglasses were less likely to wear hats and protective
clothing.96 A possible link between the use of sunglasses
and the risk of developing skin cancer, especially
malignant melanoma, has been suggested.95 The
development of UV-safe sunglasses that transmit visible
light has been suggested.95 Lenses that cut out wavelengths below 400 nm have been recommended.88
2. Wearing sunglasses under conditions of extreme albedo
(as in the Antarctic) can be associated with the
development of photokeratoconjunctivitis (‘‘snow blindness’’),97 possibly the result of inactivation of the natural
protective mechanism of squinting.98
3. As the pupil response is most sensitive to visible light,
conventional sunglasses may allow pupil dilation
in proportion to the darkness of the sunglasses99 and
increased intraocular insolation.
q 2011 Lippincott Williams & Wilkins
4. The potential decrease in low-contrast visual acuity.100
5. Spectacle frame associated reduction in visual field.101,102
6. Inconvenience—discomfort from frame, scratched lenses,
fogging, and expense. In certain sports in which participants
either are known to have a high prevalence of pterygium,
such as surfing, or where it is potentially high, such
as sailboard riding. A range of sunglasses, some of which
float, and caps have been developed; however, a casual
survey on any surfing beach in Sydney, Australia, would
suggest that these devices are not widely used. Furthermore,
there are other sports such as tennis or cricket where sun
exposure may be substantial and sunglasses are inconvenient
because of rapid, sudden movements or perspiration resulting
in fogging or lens grime. The participants of these sports
often play unprotected and would benefit from a more
sophisticated protective strategy. In this setting, UV-blocking
contact lenses may play a role because they typically span the
limbus and are currently the most effective means of reducing
if not eliminating peripheral light foci (vide infra).
Sunglass styles vary considerably, particularly because until recently
various Standards have not addressed the issue of side protection.103
Standard-setting groups are just starting to recognize that lateral
protection afforded by sunglasses is of considerable importance.
As a consequence, side protection can vary from extremely
effective to nonexistent. Even with wraparound-style sunglasses,
side exposure can still be considerable. Thus, in one study, the
movement of the sunglass frame 6 mm from the forehead resulted in
the variation of the percentage of UV reaching the eyes ranging
from 3.7% to 44.8%.104 It was found that the amount of attenuation
is highly variable and depends mainly on their size, shape, and
wearing position of the spectacles.
CONTACT LENSES
A better understanding of the advantages offered by UVblocking contact lenses in relation to the specific ocular advantage
7
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Eye & Contact Lens ! Volume 0, Number 0, Month 2011
M. Coroneo
of shielding the limbus to prevent PLF,32,33 and the development
of better contact lenses105–108 has resulted in renewed interest in this
area. These contact lenses have been available for many years,109
but have not been widely adopted109,110 perhaps because of the long
lag-time111 between UV exposure and disease manifestation. We
have confirmed that PLF focusing is greatly attenuated by the
use of UV-absorbing contact lenses.32 The UVA and UVB sensors
were placed on the nasal limbus of a model eye that was mounted in
the orbit of a mannequin head and exposed to sunlight in three
insolation environments within the region of Sydney, Australia. The
temporal limbus was exposed to a UV light source placed at various
angles behind the frontal plane, and PLF was quantified with the
sensor output. The PLF for UVA and UVB was determined with
no eyewear, with sunglasses and with commercially available soft
contact lenses, with and without UV-blocking capability.
The intensity of UVA peaked at an incident angle of
approximately 120!, the level at which the UVB response was
also at its maximum.32 The intensification of UVA was up to 318.3.
Ultraviolet-blocking contact lens reduced the intensity of PLF for
UVA and UVB by an order of magnitude, whereas clear contact
lenses showed little effect. Only the UV-blocking contact lens
achieved a significant reduction of UVA and UVB irradiance in
urban, beach, and mountain locations. The use of UV-blocking
contact lenses, as a supplement to sunglasses with appropriate UVblocking properties, provides safe, effective, and inexpensive
protection of the cornea, limbus, and crystalline lens, in settings in
which wearing sunglasses or hats is undesirable or impractical.
Contact lenses can offer UV protection against all angles of
incidence, including the peak-response angle; however, the
conjunctiva and the eyelids would require additional protection.
Conventional advice is to wear sunglasses and an adequate hat, yet
in the Sanya Eye Study, it was evident that wearing a hat (without
glasses) does not offer sufficient protection. In this study, pterygium
prevalence was 75%, and of those surveyed, 96% wore hats, and
less than 10% wore sunglasses.112
ROLE OF DIET
Early studies have linked choline deficiency,113 and pellagra,114
deficiency of niacin (vitamin B3) with development of pterygium,
but further studies have not been conducted. Because inflammation
is associated with pterygium growth and symptoms and medical
treatments that safely suppress inflammation can stabilize this
disease, it is possible that the anti-inflammatory attributes
of Mediterranean and traditional diets may play a role in protecting
against the severity or progression of this illness.115 Choline (and
a metabolite, betaine) has been identified as a likely antiinflammatory component of the Mediterranean diet.116,117 It
is possible that sunlight-induced processes such as oxidative stress
either in the skin or in the eye would trigger inflammation that
would be less well countered in choline deficiency.115 It has been
suggested that the low rates of melanoma found in Mediterranean
countries could be partly because of a protective effect of the
Mediterranean diet.118,119 After carefully controlling for several sun
exposure and pigmentary characteristics, a protective effect for
weekly consumption of fish, shellfish, drinking tea daily, and a high
consumption of vegetables, in particular carrots, cruciferous and
leafy vegetables and fruits, and of these in particular citrus fruits,
was found.119 Because the incidence of skin cancer is increasing
8
despite the use of externally applied sun protection strategies, it has
been proposed119 that nutrients reducing photo-oxidative damage
could play a beneficial role in skin cancer prevention. As penetrating
photo-oxidative UVA radiation reduces skin and blood antioxidants
and damages cell components, dietary antioxidant vitamins,
minerals, and phytochemicals, in addition to n-3 polyunsaturated
fatty acids, n-9 monounsaturated fatty acids, and low proinflammatory n-6 polyunsaturated fatty acids, have demonstrated
protective properties.119 This study concluded that the presence
of these substances in the traditional Greek-style Mediterranean diet
might have contributed to the low rates of melanoma in the
Mediterranean region despite high levels of solar radiation.
It has also been suggested that sunlight-induced dermal
production of vitamin D may play a role in the benefits of
a Mediterranean lifestyle.120 Although this must be balanced against
risk (vide infra), this diet may be protective against the development
of not only melanoma but also nonmelanoma skin malignancy.121
There is strong circumstantial evidence122–124 that omega-3 fatty
acids are also protective against the development of the nonmelanoma skin cancers, such as basal cell and squamous cell
carcinomas, that can affect both the eyelids and ocular surface.
Vitamin D may also reduce UV-induced DNA damage in skin,125
and there is evidence that a process regulated by the Vitamin D
receptor may regulate genoprotection against carcinogenic mutagens in the skin, perhaps involving stem cell populations in the
follicle.126 This may be important in pterygium pathogenesis in that
pterygium has been reported in diseases in which there is a deficient
ability to repair damage caused by UV light such as xeroderma
pigmentosum127 and perhaps Cockayne syndrome.128
Thus !internal" protection through dietary and nutritional
supplementation could complement the !external" sun-protection
strategies that should be in place.115 Yet, we now seem to
be sending mixed messages in relation to sun exposure in relation
to health. Vitamin D deficiency has become of increasing interest
because of its association with many common disease processes and
also because of an apparent increase in prevalence—it has been
referred to as a world pandemic.129 Humans have evolved to depend
on the sun for their vitamin D requirements (wavelengths between
270 and 300 nm130), and although some foods naturally contain
vitamin D, foods that are fortified with vitamin D are often
inadequate to satisfy vitamin D requirements.131,132 It is the view
of some individuals that recommendations for the avoidance of all
sun exposure has put the world’s population at risk of developing
vitamin D deficiency.129,131 In Australia, where a dramatic increase
in skin cancer rates resulted in the promotion of never exposing the
skin to direct sunlight without sun protection—clothing
or sunscreen, the so-called ‘‘sun-safe’’ message, resulted in
a marked increase in the risk of developing vitamin D deficiency.133
A recent review134 has concluded that sunscreen, in the manner used
by the general public, does not cause vitamin D insufficiency.
It identifies that implementing guidelines suggesting that sun
exposure duration for sufficient vitamin D production is limited
by the complex interaction of contributory factors and that
no recommendation can be made that is both safe and accurate
enough for general public usage.
There is thus a need to balance the risk of skin cancer and the
ophthalmohelioses from too much sun exposure with maintaining
adequate vitamin D levels to maintain general health, including
maintaining bone mass and perhaps avoiding myopia by avoiding
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too little sun exposure. The eye may play a role in this process—if
we can teach children and teenagers about early sun-related eye
damage,93 it may be possible to give a personalized recommendation to changes in their lifestyle. This approach has the possibility
of reducing morbidity, mortality, improving quality of life, and
reducing the cost to society of diseases that may well prove to
be avoidable.
ACKNOWLEDGMENTS
Much of the work summarized in this overview is the result of
long-term collaborations with Denis Wakefield, Nick di Girolamo,
Jeanie Chui, and David Mackey. Jeanie Chui provided assistance
with Figure 3 and its description.
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